This proposal involves the development of radiolabeled catechol-O-methyltransferase (COMT) inhibitors for positron emission tomography (PET) studies of the enzyme system in vivo. COMT regulates the concentration of neurotransmitters in the central and peripheral nervous systems and is an important molecular target in the development of drugs to treat Parkinson's disease (PD) since its metabolism of L-DOPA limits drug bioavailability. COMT is distributed throughout the body and brain, and abnormalities in its activity may be associated with neurological, psychiatric and cardiovascular disorders. It is also elevated in breast cancer tissue where it plays a role in estrogen metabolism. There is limited information on the regional distribution of COMT or of changes in its activity occurring in diseases. The Brookhaven PET Group has recently developed a synthetic route to F-18-labeled Ro41-0960, a potent and selective COMT inhibitor. Initial PET studies demonstrated its ability to label the COMT sites in organs such as kidney, liver and heart. The goals of this proposal are to further characterize F-18-Ro41-0960 as a tracer for peripheral COMT in vivo; synthesize and characterize C-11- labeled Ro40-7592, a COMT inhibitor used clinically to treat PD; and to examine the pharmacodynamics of COMT inhibition wih PET. Proposed studies include the measurement of baseline COMT distribution and the assessment of the sensitivity of the radiotracers to changes in COMT activity. The hypothesis is that labeled COMT inhibitors will map COMT in vivo, and the hypothesis will be tested by a complementary ex vivo approach in which radiotracer uptake will be correlated with COMT activities in rodents. The proposed studies will provide the first functional maps of COMT in the primate, thus affording a scientific tool for the investigation of COMT in living systems along with potential applications to drug development and oncology.